PAC-1 / Vanquish Oncology - LARVOL DELTA

Rational design of novel procaspase-3 activators for the targeted therapy of triple-negative breast cancer. (PubMed, Bioorg Chem) - "Density functional theory calculations confirmed their enhanced zinc-binding affinity, with adsorption energies (Eads) of -14.8332 eV (F17) and -14.8797 eV (F21), compared to -12.7474 eV for PAC-1, along with stronger electrostatic potential minima (-67.20 and -66.99 kcal/mol, respectively)...Importantly, in vivo neurotoxicity assessments revealed no significant neuronal damage at doses up to 50 mg/kg, underscoring their improved safety profile over earlier activators. These results establish F21 as a particularly promising preclinical candidate and provide a rational framework for developing target-specific, neurotoxicity-sparing procaspase-3 activators for TNBC therapy."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CASP3

A fasting-mimicking environment enhances procaspase-activating compound 1 in 2D and 3D glioma cell models. (PubMed, Cell Cycle) - "Additionally, we discovered that serum restriction was primarily responsible for the FME-induced PAC-1 enhancement. These finding are the first to demonstrate that fasting-mimicking conditions sensitize 2D and 3D glioma cell models to PAC-1, supporting the use of short-term fasting as a low-cost and widely accessible strategy for enhancing cancer therapies."

Journal • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor

A clinical-stage oncology compound selectively targets drug-resistant cancers. (PubMed, bioRxiv) - "Consequently, PAC-1 induces progressive iron depletion and selective cytotoxicity in otherwise drug-resistant MDR1-expressing cancer cells. Together, these findings redefine PAC-1's mechanism-of-action and establish a framework for exploiting multidrug resistance as a therapeutic vulnerability through targeted iron starvation."

Journal • Immunology • Oncology • ABCB1

Artificial intelligence analysis applied to the treatment of granulosa cell tumors of the ovary. (PubMed, Front Artif Intell) - "Combining tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-producing oncolytic viruses with procaspase-3 activator (PAC-1) presents a promising therapeutic strategy, as TRAIL initiates apoptosis while PAC-1 amplifies caspase activity...This integrative approach provides mechanistic insight into tumor behavior while improving predictive accuracy, supporting the development of personalized therapeutic strategies for GCTs. The framework also offers broader applicability to other cancers with limited treatment options and heterogeneous responses."

IO biomarker • Journal • Oncology • Ovarian Cancer • Solid Tumor • CASP3

Cafeic acid benzylidene hydrazides as novel procaspase-3 activators: Rational design, synthesis, and mechanistic evaluation of antitumor efficacy. (PubMed, Bioorg Chem) - "By hybridizing this natural product scaffold with optimized structural elements from PAC-1, a reference procaspase-3 activator, 28 target compounds (K-01 ∼ K-28) were successfully synthesized...These results demonstrate that the hybrid molecular design strategy effectively combines the pharmacophoric advantages of both natural products and synthetic activators. The developed procaspase-3 activators exhibit improved therapeutic potential and represent promising candidates for further development as targeted anticancer agents modulating the caspase-3 activation pathway."

Journal • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CASP3

Machine learning on transcription factor expression profiles for precision breast cancer therapy. (PubMed, Cancer Cell Int) - "These insights will open the door to delivering cutting-edge MDTS strategies to customizing breast cancer therapies."

IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor

Deciphering CD47-Mediated Platelet-Tumor Crosstalk and Its Role in NSCLC Metastasis (IASLC-WCLC 2025) - "Binding assays utilized GP1b-b and CMFDA as markers for platelets, while JON/A and Pac-1 were used as activation markers...As such, CD47 blockade could antagonize lung tumor growth and progression through multiple mechanisms. Future experiments will include studies to characterize platelet activating factors secreted by wildtype and CD47 KO cells, and in vivo experiments to understand the effects of platelet depletion on cancer cell metastasis in additional NSCLC models."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD47

ImmuProgML: machine learning-based dissection of cancer-immune dynamics during tumor progression to improve immunotherapy. (PubMed, J Transl Med) - "ImmuProgML offers a promising avenue for understanding the intricate relationship between tumors and the immune system, providing a machine learning framework for personalized cancer immunotherapy selections."

Biomarker • IO biomarker • Journal • Cognitive Disorders • Immunology • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CXCR4 • PRKCB

PAC-1 Synergizes with Sunitinib to Enhance Cell Death in Pancreatic Neuroendocrine Tumors. (PubMed, ACS Pharmacol Transl Sci) - "Our data show that PAC-1 modulates sunitinib-induced autophagy and blocks lysosomal trapping, potentiating sunitinib activity and increasing death of cancer cells. As both drugs are well-tolerated in patients, the data suggest evaluation of the PAC-1/sunitinib combination in a clinical trial of patients with PNET."

Journal • Endocrine Cancer • Neuroendocrine Tumor • Oncology • Pancreatic Cancer • Solid Tumor • CASP3

Multi-omic analyses reveal PTPN6's impact on tumor immunity across various cancers. (PubMed, Sci Rep) - "Drug sensitivity analysis identified specific drugs, including PAC-1, SNX-2112, BELINOSTAT, VORINOSTAT, TPCA-1, and PHA-893,888, whose efficacy may be influenced by PTPN6 expression. Knocking down PTPN6 expression inhibited the proliferation and migration of colorectal cancer cells in vitro, confirming its oncogenic role in this cancer type. This pan-cancer analysis establishes PTPN6's multifaceted influence on tumor immunity and its potential as a biomarker and therapeutic target."

Journal • Brain Cancer • CNS Tumor • Colorectal Cancer • Glioblastoma • Melanoma • Oncology • Sarcoma • Solid Tumor • PTPN6

Influence of sodium ferulate on neutrophil extracellular traps-platelet activation-mediated endothelial dysfunction in immune small vasculitis. (PubMed, Cytojournal) - "In addition, relative expression levels of von Willebrand Factor, β-TG, and iNOS and serum concentrations of PAC-1, β-TG, and iNOS were inhibited. Sodium ferulate can treat AAV by inhibiting NET release and platelet activation and reducing endothelial cell damage."

Journal • ANCA Vasculitis • Immunology • Oncology • Vasculitis • MPO • SELP • TNFA

Elucidating the role of pyrimidine metabolism in prostate cancer and its therapeutic implications. (PubMed, Sci Rep) - "Drug sensitivity analysis further demonstrated that tumors with elevated pyrimidine metabolism displayed increased responsiveness to several chemotherapeutic agents, including BI-2536, JW-7-24-1, and PAC-1, suggesting that targeting pyrimidine metabolism may enhance treatment efficacy. In conclusion, pyrimidine metabolism plays a critical role in prostate cancer progression, influencing immune infiltration and drug sensitivity. Targeting this metabolic pathway offers a promising strategy for the development of new therapeutic approaches, particularly for overcoming drug resistance and improving outcomes in patients with advanced prostate cancer."

Journal • Tumor mutational burden • Genito-urinary Cancer • Metabolic Disorders • Oncology • Prostate Cancer • Solid Tumor • CD4 • RRM2 • TMB

"PROGNOSTIC VALUE OF THE PERIOPERATIVE PLATELET FUNCTION AND PLATELET COUNT IN RELATION TO LIVER REGENERATION AFTER LIVER RESECTION- AN EXPLORATIVE COHORT TRIAL (VOLUTHROMB-TRIAL)" (AASLD 2024) - "For flow-cytometric tests, surface markers as CD41, PAC-1, CD62P, CD63 were used as well as Mecaprin uptake and release – each as basic test and after stimulation with TRAP-6 and ADP... Most patients undergoing hepatic surgery present with impaired thrombocyte function with risk for reduced liver regeneration and impaired outcome."

Anesthesia • Biliary Cancer • Cardiovascular • Cholangiocarcinoma • Diabetes • Fibrosis • Gastroenterology • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immunology • Liver Cirrhosis • Liver Failure • Metabolic Disorders • Oncology • Solid Tumor • CD63 • ITGA2B • SELP

Differential Effect of Omega-3 Fatty Acids on Platelet Inhibition by Antiplatelet Drugs In Vitro. (PubMed, Int J Mol Sci) - "The antiplatelet drugs aspirin and triflusal, inhibitors of cyclooxygenase-1 (COX-1); ticagrelor, an inhibitor of the receptor P2Y12; vorapaxar, an inhibitor of the PAR-1 receptor, were combined with DHA or EPA and evaluated against in vitro platelet aggregation induced by agonists arachidonic acid (AA), adenosine diphosphate (ADP) and TRAP-6. We further investigated procaspase-activating compound 1 (PAC-1) binding and P-selectin membrane expression in platelets stimulated with ADP and TRAP-6...The antiplatelet drugs exhibited heterogeneity regarding their effect on P-selectin and αIIbβ3 membrane expression, while both omega-3 PUFAs inhibited the membrane expression of αIIbβ3, though had no effect on P-selectin expression induced by ADP or TRAP-6. The combinatory effect of DHA and EPA with the antiplatelet drugs did not result in enhanced inhibitory activity compared to the sum of the individual effects of each component."

Journal • Preclinical • Cardiovascular • Dyslipidemia • Hypertriglyceridemia • Inflammation • Metabolic Disorders

Study on the sensitizing effect of SM-1 combined with irradiation on head and neck squamous cell carcinoma. (PubMed, Int J Radiat Biol) - "Derived from PAC-1, SM-1 can activate procaspase-3 and induce apoptosis in cancer cells to exert anti-tumor effects...Meanwhile, anti-tumor effect of SM-1 on HNSCC was higher than that of Debio1143, and the radiosensitivity of cells was greatly increased...In vivo, SM-1 combined irradiation showed a good anti-tumor effect. SM-1 enhances HNSCC cell radiation sensitivity in vitro and in vivo, supporting its potential as a radiosensitizer for clinical trials in combination with radiotherapy."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CASP3 • CCNB1 • CDK1

Improving platelet function following prophylactic platelet transfusion in patients with hematological malignancies (ISTH 2024) - "Overall, 50 patients who received prophylactic platelet transfusion were enrolled. CD42b expression increased, while CD41 expression decreased after transfusion. Apheresis platelets exhibited the lowest expression of PAC-1 and P-selectin when exposed to agonist stimulations."

Clinical • Hematological Disorders • Hematological Malignancies • Oncology • ITGA2B

Lupus Anticoagulant-positive Patients with Thrombosis History have Altered Glycoprotein IIbIIIa Levels (ISTH 2024) - "Surface levels of CD41, CD61, and CD62P, and fibrinogen binding to the activated CD41/CD61 complex were assessed from platelet-rich plasma before and after addition of ADP (c=15 µM) using a PAC-1 antibody... Twenty LA+TE+, 10 LA+TE- patients and 30 HCs were investigated (Tab.1). LA+TE+ patients, but not LA+TE-, exhibited significantly increased basal CD41 (+24%, p=0.026) and CD61 (+18%, p=0.018) levels compared to HCs (Fig.1A-B). Upon activation with ADP, CD41 and CD61 expression increased across all three groups, with a smaller increase of CD41 in LA+TE+ compared to HCs (8% and 13%, p=0.038), but similar in LA+TE- and HC (11%, p=0.450)."

Clinical • Cardiovascular • Hematological Disorders • Immunology • Infectious Disease • Inflammatory Arthritis • Lung Cancer • Novel Coronavirus Disease • Oncology • Solid Tumor • Thrombosis • ITGA2B • ITGB3 • SELP

Platelet functional activity in pediatrics patients with acute myeloid and lymphocytic leukemia (ISTH 2024) - "Agonist-induced aggregation was significantly lower in both study groups compared to control. AL patients had enhanced basal GPIIb/IIIa activation (% of PAC1+ platelets), whereas the levels of GPIIb/IIIa and its active form (PAC-1) were significantly reduced after activation. Agonist-induced degranulation of both α- and δ-granules was lower in both AL groups compared to control, and AML patients had a tendency for lower granule secretion."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • ANXA5 • CD63 • ITGA2B • SELP

Improving platelet function following prophylactic platelet transfusion in patients with hematological malignancies. (PubMed, Int J Lab Hematol) - "Prophylactic transfusion improved platelet function. Platelet function significantly improved in patients with a CCI >4500, those with the same blood types as that of apheresis platelets, or those with platelet-derived microparticle levels <4.7%. No significant improvement in platelet function was noted after the transfusion of different blood types with acceptable compatibility or the transfusion of incompatible blood types. Our results suggest that transfusing platelets with the same blood type remains the optimal choice."

Journal • Hematological Disorders • Hematological Malignancies • Oncology • Thrombocytopenia • ITGA2B

Small molecule procaspase activating compound 1 (PAC-1) enhances CAR-T immunotherapy for solid tumors in syngeneic murine models (AACR 2024) - P1 | "Taken altogether, our results demonstrate that PAC-1 engages the immune system to treat cancer by inducing expression of pro-inflammatory cytokines in tumor cells allowing the recruitment of CD8+ effector T cells to the tumor microenvironment. Combination strategies that boost T cell trafficking shows great promise to enhance the anti-tumor efficacy and feasibility of adoptive CAR-T therapy against solid tumors."

IO biomarker • Late-breaking abstract • Preclinical • Tumor mutational burden • Oncology • Ovarian Cancer • Solid Tumor • CASP3 • CD8 • MUC1 • PDPN • TMB

Synthesis of Novel Nilotinib Analogues and Biological Evaluation of Their Antiplatelet Activity and Functionality towards Cancer Cell Proliferation In Vitro. (PubMed, Pharmaceuticals (Basel)) - "A platelet aggregation assay was performed, and the expression of P-selectin and PAC-1, as well as the effect on the proliferation of healthy endothelial cells, were evaluated. All the analogues reduced the expression of E- and N-cadherin in different amounts, while the analogues-1 and -3 exhibited similar antimigratory effects on HepG2 cells. The results of this study reveal considerable potential to develop new tyrosine kinase inhibitors with improved antiplatelet and antitumor properties."

Journal • Preclinical • Cardiovascular • Chronic Myeloid Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Thrombosis • ABL1 • BCR • CDH1 • CDH2

Immune Checkpoints are Upregulated on Activated Platelets and Monocytes (GTH 2024) - "Platelets were identified based on side-scatter properties and expression of CD41, P-selectin, PAC-1, CD63, PD1 and PDL1...Based on these findings, we are currently assessing monocyte and platelet activation and PDL1 expression in cancer patients before and under ICI. Our ultimate goal is to investigate if monocytes and platelets become activated under ICI, hence resulting in ICI-induced thromboinflammation, and to assess the impact of platelet and monocyte PDL1 expression on treatment outcome"

IO biomarker • Cardiovascular • Hematological Disorders • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Venous Thromboembolism • CD14 • CD40 • CD63 • ITGA2B • ITGB3 • PTPRC

Ayurvedic preparations of Raudra Rasa inhibit agonist-mediated platelet activation and restrict thrombogenicity without affecting cell viability. (PubMed, FEBS Open Bio) - "Here we demonstrate that Raudra Rasa and its derivatives significantly reduce thrombin-induced integrin activation and granule secretion in platelets, as observed by reduced PAC-1 binding and P-selectin externalization, respectively...Consistent with the above, Raudra Rasa significantly reduced thrombin-induced tyrosine phosphorylation of the platelet proteins, as well as phosphorylation of enzymes AKT and GSK-3β. In summary, Raudra Rasa inhibits agonist-mediated platelet activation without affecting cell viability, suggesting it may have therapeutic potential as an anti-platelet/anti-thrombotic agent."

Journal • Oncology

Mathematical modeling predicts pathways to successful implementation of combination TRAIL-producing oncolytic virus and PAC-1 to treat granulosa cell tumors of the ovary. (PubMed, Cancer Biol Ther) - "Encouragingly, our results suggest that increases to the OV infection rate can lead to the success of this combination therapy within a year. The model developed here can continue to be improved as more data become available, allowing for regimen-tailoring via virtual clinical trials, ultimately shepherding effective regimens into trials."

Journal • Oncolytic virus • Infectious Disease • Oncology • Ovarian Cancer • Solid Tumor

Study of PAC-1 and Entrectinib for Patients With Metastatic Uveal Melanoma (clinicaltrials.gov) - P1/2 | N=6 | Terminated | Sponsor: Arkadiusz Z. Dudek, MD | Phase classification: P1b/2 ➔ P1/2 | Active, not recruiting ➔ Terminated; This study required dose reductions to the lower dose level (Dose level -1). But this dose level (Dose level -1) was not further explored because of lack of funding.

Phase classification • Trial termination • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma